Many industries require that their solid particulate raw materials meet rigorous specifications as to size and shape. Some require very small particles or crystals with closely defined limitations as to the range of size and shape.
In the food industry, it would be advantageous to obtain raw materials as solid particulate powders having very small, narrowly distributed mesh sizes in order to distribute more evenly the flavour ingredient throughout their prepared food-stuff products.
Industries concerned with colour in the form of dye-stuffs and pigments need small, uniform, closely defined particulate materials, to distribute better and more evenly such dyes and pigments in suspension or solution throughout their paints, printing inks and textile printing media.
The plastics industry also has need for very small particles of a variety of polymeric materials such as polystyrene, polyvinyl chloride, polyacrylamide etc.
The property known as polymorphism is the ability of crystalline materials to exist in a variety of forms or structures despite being chemically indistinguishable from each other. The crystalline form or structure may have an effect on the properties of the material. In view of this, in addition to the control of the particle size (mesh) of their raw materials, some industries require crystals of very well defined shape to the rigorous exclusion of similarly sized crystals of other shapes.
The chemical and pharmaceutical industries have a particular demand for small particles for a wide range of applications. For example, small particle size raw ingredients and intermediates are advantageous for their increased ease of dissolution, enhanced chemical reactivity and increased ease of drying.
The pharmaceutical industry in particular has a significant requirement for use of particles of controlled size in drug formulations. There are several methods available for provision of controlled drug delivery systems. Particle size and crystal form are important characteristics affecting the performance and efficacy of ingested pharmaceuticals, whether as tablets, powders or suspensions. Small particles of micro-crystalline form, due to their large surface area, are absorbed more quickly than larger particles and hence have a faster activity. The reverse is also true. Therefore, the release rate of active ingredients can be controlled by controlling the size of the particles from which the pharmaceutical is made.
Particle size control is also important in situations where a drug is delivered through the skin in, for example, the provision of painkillers and vaso-dilators, such as capsicum extracts, used as a means of treating and accelerating the healing of sprains and muscular damage. Suppositories, which depend for their efficacy on the ability of the active pharmaceutical to penetrate through the rectal mucosa, have proved to be a valuable means for the administration of drugs. The opinion that “skin-patches” comprising or impregnated with pharmaceutically active compounds may have considerable advantages has been growing in popularity in recent years. Hormone replacement therapy patches and nicotine patches are now a widely used and effective means for the delivery of active molecules through the epidermis.
In some applications where prolonged drug delivery is desired, such as in certain common cold preparations, a mixture of variously sized particles is used in order that the therapeutic benefits last for extended periods of time.
Traditionally, milling or grinding of a solid material was considered to be an adequate means for causing attenuation or reduction in the particle size of a solid material. Micronization improved this technique, yielding even smaller particles.
Unfortunately, all forms of mechanical grinding, milling, micronizing or attrition of solids to powders result in the destruction of the crystal form and in the introduction to the powder of heat energy with an inevitable rise in temperature of the solid. This may (at best) have no effect on the pharmacologically active ingredient. However, it may in some cases cause a reduction in the efficacy of a preparation containing the active ingredients.
Methods including introducing liquid nitrogen or solid carbon dioxide to the grinding surfaces, collectively known as “freeze grinding”, have gone some way to alleviating and evading such rises in temperature, by removing the heat almost as fast as it is generated. However, even this process can never be performed without destruction of the crystalline form of a material.
Another means for the production of small particles from solutions of a compound is “spray drying”. This process has been widely used for over forty years as a means of producing small particles of the water soluble solids of coffee liquor to yield the product known as “instant coffee”.
According to this technique, a hot (frequently super-heated) aqueous solution containing the compound, is injected at high velocity into a large chamber through an “atomiser” or orifice, with the intention of producing very small droplets. The droplets fall under the influence of gravity whilst encountering a spiral and rising stream of warm dry air, injected into the chamber at the base thereof. As the warm air passes up through the chamber counter-current to the falling droplets of solution, heat is exchanged, and, drying of the droplets occurs. The resultant dry powder is harvested from the bottom of the chamber for further processing.
This process has disadvantages that prevent wide-scale use for the general preparation of small particles of some compounds, for example, pharmaceutically active ingredients. The introduction of heat to the injected liquor could cause decomposition of a pharmaceutically active ingredient. Exposure to air could result in the oxidation of a component. Furthermore, all components desired to be produced by this method are required to be prepared in aqueous solution, which can be difficult, if not impossible, for some components. In addition, atomisation of the formulation combined with heat and rapid drying often introduces static energy into the particles, thus increasing the risk of fire and causing the particles to be hygroscopic.
In recent years, a technique analogous to spray-drying, but using super-critical carbon dioxide fluid as a solvent has been under intense scrutiny by many industries.
This technique relies on the curious property of carbon dioxide (at temperatures above its critical temperature of 31° C.) and at very high pressures (in the region of 100 to 400 Bar) to “dissolve” certain pharmaceuticals and other materials such as essential oils, fragrances and flavours. To use this procedure for the production of very small particles, a solute (e.g. the active pharmaceutical) is placed in a chamber capable of withstanding pressures in excess of 300-500 Bar. The chamber and contents are heated to typically 30-40° C. and the solute is contacted with and subjected to a flow of carbon dioxide at pressures that are typically 100-400 Bar. Some of the solute appears to “dissolve” in this super-critical fluid stream.
If the super-critical solution stream is allowed to emerge into a second chamber, wherein the pressure is maintained at a lower level or even at atmospheric pressure, the dissolving properties of the carbon dioxide are reduced or eliminated and a cloud of very fine particles of solute is formed as a mist. It is sometimes possible to harvest this mist and thereby make a preparation of very finely divided solute.
One-major disadvantage of this procedure is its cost; the capital cost of the various chambers, pumps, nozzles, heat exchangers etc., all of which must be capable of withstanding and functioning under very high pressures indeed, is extremely high.
Furthermore, carbon dioxide, being an acidic gas, can cause reductions in pH of the solute, in the presence of water, to unacceptably low levels.
It is an object of the present invention to address problems associated with the production of solid particles.